Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis

Ana Lleo, Christopher L. Bowlus, Guo Xiang Yang, Pietro Invernizzi, Mauro Podda, Judy Van De Water, Aftab A. Ansari, Ross L. Coppel, Howard J. Worman, Gregory James Gores, M. Eric Gershwin

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Abstract

Our understanding of primary biliary cirrhosis (PBC) has been significantly enhanced by the rigorous dissection of the multilineage Tand B cell response against the immunodominant mitochondrial autoantigen, the E2 component of the pyruvate dehydrogenase complex (PDC-E2). PDC-E2 is a ubiquitous protein present in mitochondria of nucleated cells. However, the damage of PBC is confined to small biliary epithelial cells (BECs). We have previously demonstrated that BECs translocate immunologically intact PDC-E2 to apoptotic bodies and create an apotope. To define the significance of this observation, we have studied the ability of biliary or control epithelial apotopes to induce cytokine secretion from mature monocyte-derived macrophages (MDMUs) from either patients with PBC or controls in the presence or absence of anti-mitochondrial antibodies (AMAs). We demonstrate that there is intense inflammatory cytokine production in the presence of the unique triad of BEC apotopes, macrophages from patients with PBC, and AMAs. The cytokine secretion is inhibited by anti-CD16 and is not due to differences in apotope uptake. Moreover, MDMUs from PBC patients cultured with BEC apoptotic bodies in the presence of AMAs markedly increase tumor necrosis factor-related apoptosis-inducing ligand expression. Conclusion: These results provide a mechanism for the biliary specificity of PBC, the recurrence of disease after liver transplantation, and the success of ursodiol in treatment. They further emphasize the critical role of the innate immune system in the perpetuation of this autoimmune disease.

Original languageEnglish (US)
Pages (from-to)987-996
Number of pages10
JournalHepatology
Volume52
Issue number3
DOIs
StatePublished - Sep 2010

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Biliary Liver Cirrhosis
Innate Immunity
Anti-Idiotypic Antibodies
Epithelial Cells
Cytokines
Dihydrolipoyllysine-Residue Acetyltransferase
Macrophages
Ursodeoxycholic Acid
Autoantigens
Liver Transplantation
Autoimmune Diseases
Dissection
Immune System
Mitochondria
B-Lymphocytes
Tumor Necrosis Factor-alpha
Apoptosis
Ligands
Recurrence
Proteins

ASJC Scopus subject areas

  • Hepatology
  • Medicine(all)

Cite this

Lleo, A., Bowlus, C. L., Yang, G. X., Invernizzi, P., Podda, M., Van De Water, J., ... Gershwin, M. E. (2010). Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis. Hepatology, 52(3), 987-996. https://doi.org/10.1002/hep.23783

Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis. / Lleo, Ana; Bowlus, Christopher L.; Yang, Guo Xiang; Invernizzi, Pietro; Podda, Mauro; Van De Water, Judy; Ansari, Aftab A.; Coppel, Ross L.; Worman, Howard J.; Gores, Gregory James; Gershwin, M. Eric.

In: Hepatology, Vol. 52, No. 3, 09.2010, p. 987-996.

Research output: Contribution to journalArticle

Lleo, A, Bowlus, CL, Yang, GX, Invernizzi, P, Podda, M, Van De Water, J, Ansari, AA, Coppel, RL, Worman, HJ, Gores, GJ & Gershwin, ME 2010, 'Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis', Hepatology, vol. 52, no. 3, pp. 987-996. https://doi.org/10.1002/hep.23783
Lleo, Ana ; Bowlus, Christopher L. ; Yang, Guo Xiang ; Invernizzi, Pietro ; Podda, Mauro ; Van De Water, Judy ; Ansari, Aftab A. ; Coppel, Ross L. ; Worman, Howard J. ; Gores, Gregory James ; Gershwin, M. Eric. / Biliary apotopes and anti-mitochondrial antibodies activate innate immune responses in primary biliary cirrhosis. In: Hepatology. 2010 ; Vol. 52, No. 3. pp. 987-996.
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